Not all patients with obstructive sleep apnea (OSA) develop excessive daytime sleepiness (EDS) or cardiovascular disease at any given level of disease severity. Adverse outcomes of OSA may be driven by genomic, biological, and/or environmental factors, but mechanisms remain unclear. There is a need to determine genetic and biological markers and how they may influence EDS symptoms and cardiovascular risk among patients with OSA. Our overall hypothesis is that mechanisms of sleepiness and cardiovascular disease share common molecular pathways. Thus, genetic and biological factors associated with risk for sleepiness likely predict individuals who develop adverse cardiovascular outcomes. In the K99 mentored phase of the award, genetic markers and their relationship to EDS symptoms will be determined via retrospective analysis of the ongoing Icelandic Sleep Apnea Cohort (ISAC). Advanced didactic and laboratory training in translational research will complement this analysis and build upon my prior experience with genetics and biomarker research. We hypothesize that a different frequency of polymorphisms in genes such as NOX-2, NOX p22phox, tumor necrosis factor-alpha (TNF-?), and PDE4D, will modify the degree of sleepiness symptoms in individuals with similar degrees of sleep-disordered breathing. In the R00 phase, a case-control study will be conducted to investigate further the relevant genetic markers identified in the K99 phase. We will recruit 64 sleepy and 64 non-sleepy OSA patients from the clinic population at the Penn Sleep Center to determine whether elevated genetic and biological markers are related to sleepiness symptoms. Our primary hypothesis is that patients with EDS symptoms (measured subjectively) will have increased biological and genetic markers. The secondary hypothesis is that those with EDS symptoms (subjective and objectively) will have increased biological and genetic markers compared to those with neither symptoms. Individuals seeking medical attention for OSA will be recruited for the study. Blood and urine samples will be obtained after polysomnography. EDS symptoms will also be measured by using the Epworth Sleepiness Scale (ESS) and the Psychomotor Vigilance Test (PVT). Cardiovascular risk measures [ambulatory blood pressure (ABP) and Pulse-Wave Velocity (PWV)] will also be obtained at this time. We hypothesize that the symptoms of EDS are associated with increased cardiovascular risk measures.